An epigenetic component of type 2 diabetes and other diseases in humans is widely hypothesized but lacks adequate empirical support. Animal studies show that nutritional interventions during pregnancy can affect gene-specific DNA methylation in the offspring causing obesity and hypertension. We have also described persistent epigenetic changes in humans at age 58 after prenatal exposure to the Dutch Hunger Winter famine of1944-1945 and observed an increase in obesity, diabetes, and other adverse outcomes. This study hopes to clarify the biologic mechanism that can link these observations in a study of 628 men and women with prenatal famine exposure and unexposed controls, arranged in 314 same-sex sibling pairs. First, we will generate a genome-wide catalog of Prenatally-induced Differentially Methylated Regions (P-DMRs), comparing DNA methylation profiles for all study subjects using the novel Illumina high-throughput, high content methylation chip covering over 450k CpG sites. Then we will identify in a human cadaver tissue bank the P-DMRs subsets that mark methylation in metabolically active tissues and organs. These P-DMRs will then be evaluated in relation to prenatal famine exposure and adult disease. This approach will provide further insights into the link between the prenatal environments with adult disease. PUBLIC HEALTH RELEVANCE: Narrative In this study we will utilize the unique quasi-experimental setting of the Dutch Hunger Winter to discover prenatally induced DNA methylation profiles that predict the risk of metabolic disease in humans.